Intraerythrocytic Iron Chelation: A New Therapy for Thalassemia?

Thalassemic red blood cells (RBC) are characterized by alterations in globin chain stability that result in the release of redox-active iron within the RBC. This iron, via a self-propagating and self-amplifying reaction, destabilizes additional hemoglobin (hence, releasing more iron) and causes significant oxidant damage to other cellular components. To attenuate this iron-mediated damage pharmacologically, an intraerythrocytic iron chelation shuttle system is proposed. The iron shuttle systemconsists of low affinity, RBC permeable, iron-binding agents which enter the cell, bind iron, diffuse out, and hand-off the iron to a high affinity, RBC-impermeable, high molecular weight starch derivative of desferrioxamine (S-DFO). It is proposed that interruption of the iron-dependent damage via intraerythrocytic iron chelation results in improved RBC survival and may obviate the need for the initiation of transfusion therapy in some patients. Putative shuttle agents include 2,2'-bipyridyl, 2,3-dihydroxybenzoic acid (2,3-DHB), N,N-bis(2-hydroxybenzyl)ethylene-diamine-N,N-diacetic acid, and pyridoxal isonicotinoyl hydrazone. The proposed nonpermeable terminal chelator is a high molecular weight starch derivative of desferrioxamine that exhibits prolonged vascular survival (up to 7 days) and very significantly reduced toxicity relative to unmodified desferrioxamine. As is discussed, in vitro data demonstrate that a two component iron shuttle system effectively slows iron-driven oxidative damage improving the viability of model thalassemic RBC. Further in vivo studies may prove that the intraerythrocytic iron chelation shuttle system may have therapeutic potential in the treatment of thalassemia.